Jin Guiyuan, Gao Xizhuang, Dai Fengxian, Zhang Hairong, Lu Tingting, Jing Dehuai, Yang Yonghong, Zhu Fengqin, Zhou Guangxi
Medical Research Center, Affiliated Hospital of Jining Medical University, Jining 272000, Shandong Province, China.
Jining Medical University, Jining 272000, Shandong Province, China.
Int Immunopharmacol. 2025 May 16;155:114634. doi: 10.1016/j.intimp.2025.114634. Epub 2025 Apr 10.
Nudix hydrolase 1 (NUDT1) plays a crucial role in tumours, where it helps limit cellular damage caused by reactive oxygen species. However, the exact function of NUDT1 in ulcerative colitis (UC) is not well understood.
NUDT1 expression in the intestinal mucosal tissues of patients with UC was analysed using quantitative reverse transcription polymerase chain reaction. A public database was used to analyse the expression of selected signature genes of interest in patients with UC with different NUDT1 expression levels. TH588, a potent NUDT1 inhibitor, was used to treat intestinal epithelial cells (IECs) in mice. The functions of the IECs were assessed using quantitative reverse transcription polymerase chain reaction, flow cytometry, western blotting, and fluorescence microscopy. A mouse model of dextran sodium sulphate-induced colitis was established.
We examined NUDT1 expression and found that it was significantly elevated in the colon tissues of patients with UC. A colitis model was established in wild-type mice treated with TH588, which significantly reduced intestinal mucosal inflammation and induced notable alterations in faecal microbiota composition. Moreover, TH588 helped preserve intestinal mucosal barrier function. Inhibition of NUDT1 expression in IECs enhanced antioxidant activity by increasing Nrf2 expression and reducing ERK phosphorylation, which, in turn, stabilised tight junctions in IECs exposed to oxidative stress.
Our research emphasises the role of NUDT1 in modulating the intestinal microbiota and intestinal mucosal barrier in UC, indicating that targeting NUDT1 during intestinal mucosal inflammation could serve as a promising therapeutic strategy for UC.
Nudix水解酶1（NUDT1）在肿瘤中发挥着关键作用，它有助于限制活性氧引起的细胞损伤。然而，NUDT1在溃疡性结肠炎（UC）中的具体功能尚不清楚。
采用定量逆转录聚合酶链反应分析UC患者肠黏膜组织中NUDT1的表达。利用公共数据库分析不同NUDT1表达水平的UC患者中所选感兴趣特征基因的表达。使用强效NUDT1抑制剂TH588治疗小鼠肠上皮细胞（IECs）。采用定量逆转录聚合酶链反应、流式细胞术、蛋白质印迹法和荧光显微镜评估IECs的功能。建立葡聚糖硫酸钠诱导的结肠炎小鼠模型。
我们检测了NUDT1的表达，发现其在UC患者的结肠组织中显著升高。在用TH588治疗的野生型小鼠中建立了结肠炎模型，TH588显著减轻了肠黏膜炎症，并导致粪便微生物群组成发生显著变化。此外，TH588有助于维持肠黏膜屏障功能。抑制IECs中NUDT1的表达可通过增加Nrf2表达和减少ERK磷酸化来增强抗氧化活性，进而稳定暴露于氧化应激的IECs中的紧密连接。
我们的研究强调了NUDT1在调节UC肠道微生物群和肠黏膜屏障中的作用，表明在肠黏膜炎症期间靶向NUDT1可能是一种有前景的UC治疗策略。
